Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcoma (KS) tumors, primary effusion lymphoma (PEL), and Multicentric Castleman's disease. Although classical KS has a low prevalence rate worldwide, the more aggressive endemic KS, seen primarily in Africa, accounts for nearly half of the reported cancers in some regions and is the leading cause of cancer death in those areas. Despite being a pressing human health problem, there has been little or no activity so far to develop protective and/or therapeutic vaccines against KSHV infection and its associated diseases. A current major barrier for the in vivo studies of KSHV replication, persistence, pathogenesis, and ultimately vaccine is the lack of a proper animal model. We recently performed the first successful zoonotic or cross-species transmission of KSHV into common marmosets, a New World primate (Callithrix jacchus, Cj). This preliminary study has shown that: (1) common marmosets intravenously inoculated with recombinant rKSHV.219 rapidly sero-converted and maintained a high anti-KSHV antibody response over a long period of time;(2) common marmosets infected with rKSHV.219 via the oral and/or intranasal routes also rapidly sero-converted and maintained an anti-KSHV antibody response;and (3) KSHV DNA and the latent nuclear antigen protein are readily detectable in infected animals. This is the first animal model that significantly recapitulates the important aspects of KSHV infection in humans, thus providing a unique opportunity in developing potential vaccine strategies against KSHV infection. The most impressive vaccine protections achieved to date against virus- associated diseases primarily utilize persisting, live, attenuated viruses. This may be due to the duration of the immune response elicited through the continuous expression of viral proteins from a persisting viral genome in the infected host. Thus, we will consider developing a persistent, attenuated KSHV to serve as the vaccine vector. The goal of this study is two-folds: Firstly, to develop a genetically modified replication-competent, non-pathogenic KSHV strain to be used as a vaccine candidate. Secondly, to further build up the primate model of KSHV infection and to develop immunological and virological assays for the vaccination and challenge experiments. This proposal is highly innovative and a successful outcome should prove to be a major discovery that significantly impacts the understanding of the controls of KSHV infection to ultimately reveal novel protective and/or therapeutic vaccine strategies. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcoma tumors, primary effusion lymphoma, and Multicentric Castleman's disease. Although classical KS has a low prevalence rate worldwide, the more aggressive endemic KS, seen primarily in Africa, accounts for nearly half of the reported cancers in some regions and is the leading cause of cancer death in those areas. Despite being a pressing human health problem, there has been little or no activity so far to develop protective and/or therapeutic vaccines against KSHV infection and its associated diseases. The proposed research is directed toward investigating the potential development of live-attenuated KSHV as a vaccine candidate. This proposal is highly innovative and a successful outcome should prove to be a major discovery that significantly impacts the understanding of the controls of KSHV infection to ultimately reveal novel protective and/or therapeutic vaccine strategies.